Induction of tumor-specific immunity is an attractive approach for cancer therapy because of the prospect of harnessing the body""s own defense mechanisms, rather than using standard toxic therapeutic agents, to provide long-term protection against tumor existence, growth and recurrence. This strategy is attractive for its potential to destroy small metastatic tumors which may escape detection, and to provide immunity against recurrent tumors.
In principle, an immunotherapy would depend on the presence of tumor-specific antigens and on the ability to induce a cytotoxic immune response that recognizes tumor cells which present antigens. Cytotoxic T lymphocytes (CTL) recognize major histocompatibility complex (MHC) class I molecules complexed to peptides derived from cellular proteins presented on the cell surface, in combination with co-stimulatory molecules. Mueller et al., Annu. Rev. Immunol. 7: 445-80 (1989). In fact, tumor-specific antigens have been detected in a range of human tumors. Roth et al., Adv. Immunol. 57: 281-351 (1994); Boon et al., Annu. Rev. Immunol. 12: 337-65 (1994).
Some cancer vaccination strategies have focused on the use of killed tumor cells or lysates delivered in combination with adjuvants or cytokines. More recently, gene transfer of cytokines, MHC molecules, co-stimulatory molecules, or tumor antigens to tumor cells has been used to enhance the tumor cell""s visibility to immune effector cells. Dranoff and Mulligan, Adv. Immunol. 58: 417-54 (1995).
The therapeutic use of xe2x80x9ccancer vaccinesxe2x80x9d has presented major difficulties, however. In particular, conventional approaches require obtaining and culturing a patient""s autologous tumor cells for manipulation in vitro, irradiation and subsequent vaccination, or the identification and purification of a specific tumor antigen.
It is therefore an object of the present invention to provide a method of eliciting a systemic antitumor immune response in a patient who presents with or who is at risk of developing multiple metastatic tumors without manipulating the patient""s autologous tumor cells or identifying or purifying specific antigens.
It is also an object of the present invention to provide vectors for effecting this method.
In accomplishing these and other objectives, the present invention provides a method of eliciting a systemic antitumor immune response in a patient who presents with or who is at risk of developing multiple metastatic tumors of a given cell type. In accordance with one aspect of the invention, the method comprises inoculating a tumor in the patient with a pharmaceutical composition consisting essentially of:
(A) a herpes simplex virus (HSV) that infects tumor cells but that does not spread in normal cells, and
(B) a pharmaceutically acceptable vehicle for the virus, such that an immune response is induced that is specific for the tumor cell type and that kills cells of the inoculated tumor and of a non-inoculated tumor. In accordance with one embodiment, the virus replicates in dividing cells and exhibits attenuated replication in non-dividing cells. In accordance with another embodiment, the virus is replication-defective. In accordance with yet another embodiment, the virus is conditionally replication-competent. In accordance with another embodiment, the virus is of a vaccine strain. In accordance with one embodiment, the genome of the virus comprises at least one expressible nucleotide sequence coding for at least one immune modulator.
In accordance with another aspect of the invention, the method comprises inoculating a tumor in the patient with a pharmaceutical composition comprising:
(A) a herpes simplex virus that infects tumor cells but that does not spread in normal cells, and whose immunological properties consist essentially of inducing an immune response that is specific for the tumor cell type and that kills cells of the inoculated tumor and of a non-inoculated tumor,
(B) a defective herpes simplex virus vector containing at least one expressible nucleotide sequence encoding at least one immune modulator, and
(C) a pharmaceutically acceptable vehicle for the virus and defective vector, such that an immune response is induced that is specific for the tumor cell type and that kills cells of the inoculated tumor and of a non-inoculated tumor.
In accordance with another aspect of the invention, the method comprises inoculating a tumor in the patient with a pharmaceutical composition comprising:
(A) a first herpes simplex virus (HSV) that infects tumor cells but that does not spread in normal cells, and whose immunological properties consist essentially of inducing an immune response that is specific for the tumor cell type and that kills cells of the inoculated tumor and of a non-inoculated tumor,
(B) a second herpes simplex virus (HSV) that infects tumor cells but that does not spread in normal cells, and
(C) a pharmaceutically acceptable vehicle for the viruses, such that an immune response is induced that is specific for the tumor cell type and that kills cells of the inoculated tumor and of a non-inoculated tumor.
In accordance with another aspect of the present invention, the method comprises inoculating a tumor in the patient with a pharmaceutical composition comprising:
(A) a first herpes simplex virus (HSV) that infects tumor cells but that does not spread in normal cells, wherein the genome of the first herpes simplex virus comprises at least one expressible nucleotide sequence coding for at least one immune modulator,
(B) a second herpes simplex virus (HSV) that infects tumor cells but that does not spread in normal cells, wherein the genome of the second herpes simplex virus comprises at least one expressible nucleotide sequence coding for at least one immune modulator, and
(C) a pharmaceutically acceptable vehicle for the viruses, such that an immune response is induced that is specific for the tumor cell type and that kills cells of the inoculated tumor and of a non-inoculated tumor.
In accordance with another aspect of the present invention, the method comprises inoculating a tumor in the patient with a pharmaceutical composition comprising:
(A) a herpes simplex virus (HSV) that infects tumor cells but that does not spread in normal cells,
(B) a viral vector comprising at least one expressible nucleotide sequences coding for at least one immune modulator, and
(C) a pharmaceutically acceptable vehicle for the virus and viral vector, such that an immune response is induced that is specific for the tumor cell type and that kills cells of the inoculated tumor and of a non-inoculated tumor. The viral vector may be, for example, an adenoviral vector, a adenovirus-associated vector, a retroviral vector, or a vaccinia virus vector.
Mutated viruses useful in the methods of the invention also are provided. In accordance with one aspect of the invention, there is provided a herpes simplex virus that is incapable of expressing both (i) a functional xcex334.5 gene product and (ii) a ribonucleotide reductase, wherein the genome of the virus comprises at least one expressible nucleotide sequence encoding at least one immune modulator. In accordance with another aspect of the invention, there is provided a herpes simplex virus ICP4 mutant tsK, the genome of which has been altered to incorporate at least one expressible nucleotide sequence coding for at least one immune modulator.
Compositions for effecting the methods of the present invention also are provided. In accordance with one aspect of the invention, a composition for eliciting a systemic antitumor immune response in a patient who presents with or who is at risk of developing multiple metastatic tumors of a given cell type comprises:
(A) a herpes simplex virus that is incapable of expressing both (i) a functional xcex334.5 gene product and (ii) a ribonucleotide reductase, and
(B) a defective herpes simplex virus vector containing at least one expressible nucleotide sequence encoding at least one immune modulator.
In accordance with another aspect of the invention, a composition for eliciting a systemic antitumor immune response in a patient who presents with or who is at risk of developing multiple metastatic tumors of a given cell type comprises:
(A) a herpes simplex virus that is replication-defective, and whose immunological properties consist essentially of inducing an immune response that is specific for the tumor cell type and that kills cells of the inoculated tumor and of a non-inoculated tumor, and
(B) a defective herpes simplex virus vector containing at least one expressible nucleotide sequence encoding at least one immune modulator.
In accordance with yet another aspect of the invention, a composition for eliciting a systemic antitumor immune response in a patient who presents with or who is at risk of developing multiple metastatic tumors of a given cell type comprises:
(A) a herpes simplex virus that is conditionally replication-competent, and
(B) a defective herpes simplex virus vector containing at least one expressible nucleotide sequence encoding at least one immune modulator.
These and other objects and aspects of the invention will become apparent to the skilled artisan in view of the teachings contained herein.